Abstract
We wish to report here an efficient methodology for the preparation of (S)-4-[(methoxycarbonyl)methyl]-2-azetidinone by chemicoenzymatic approach starting from citric acid derivative (Scheme II). Dimethyl β-aminoglutarate (4) has been chosen as our starting material. It was prepared in excellent yield by reductive amination of dimethyl β-oxoglutarate. Pig liver esterase hydrolyzed 4 very efficiently, but (3R)-half-ester R-3 was formed in low optical yield. Therefore, the amino group was protected by the benzyloxycarbonyl (Z) group with ZCl, affording 5. Surprisingly, incubation of 5 with pig liver esterase at the same reaction condition afforded (3S)-half-ester 6. Hydrogenolysis of 6 afforded quantitatively S-3. It was converted to monocyclic β-lactam S-2 with Ph_3P-(PyS)_2-CH_3CN system, affording (S)-4-[(methoxycarbonyl)methyl]-2-azetidinone in high optical purity. The new and efficient methodology for the formation of β-lactam compounds from β-amino acids has been also developed by the present research by using Ph_3P-(PyS)_2-CH_3CN system. The methodology was successfully applied to β-alanine, dl-3-amino-3-phenylpropionic acid, dl-3-benzylaminobutyric acid, 3-benzylaminopropionic acid, and dl-2,3-diaminopropionic acid, affording the corresponding β-lactams in good to excellent yields. On the other hand, negamycin, an antibiotic possessing a strong inhibitory activity against resistent Gram-negative bacteria including Pseudomonas, was also synthesized by chemico-enzymatic approach, using the same key intermediate S-3 (Scheme III). A key feature of the present methodology is the enzyme-induced generation of key chiral intermediates from a symmetric starting material and the selective elaboration of biologically significant enantiomers.
